A family of potassium selective ion channels, including four transmembrane domain, dual pore domain potassium (K+) channels (4T/2P)—TWIK, TREK, TASK-1, TASK-2 and TRAAK—are involved in the control of background membrane conductance associated with various potassium driven sensory responses, such as anti-pain (Curr Neuropharmacol. 2010 September; 8(3): 276-286). These channels are interesting targets for consumer products aiming to deliver anti-pain/irritation or provide overall comfort benefits. Within this group, TWIK-1, TREK-1, TASK-1 and TASK-2 are widely distributed in many different tissues, while TRAAK is present exclusively in brain, spinal cord and retina (The Journal of Neuroscience, 2001 21(19):7491-7505). The 4T/2P channels have different physiologic properties; TREK-1 channels, are outwardly rectifying (Fink et al. (1996) EMBO J 15(24):6854-62), while TWIK-1 channels, are inwardly rectifying (Lesage et al. (1996) EMBO J 15(5):1004-11. TASK channels are regulated by changes in pH while TRAAK channels are stimulated by arachidonic acid (Reyes et al. (1998) JBC 273(47):30863-30869).
Members of the two-pore family of K+ channels have a variety of properties, ranging from acid-sensitivity to anesthetic sensitivity. TREK-1, TREK-2, and TRAAK are members of the two-pore family that are activated by a variety of conditions, including membrane stretch, pH, cell swelling, shear stress or negative pressure.
K+ channels are involved in multiple different processes and are important regulators of homeostasis in nearly all cell types. Their relevance to consumer product interaction with the consumer and their role in many human diseases, suggests that consumer products could be designed to target specific channel subtypes. Agonists to these channels have yet to see use in pharmaceutical applications, as the presently available channel agonists tend to be non-specific and elicit both positive and negative responses, thereby reducing clinical efficacy. Other agonists to two-pore-domain K+ channel family members that may be used in consumer products include agonists to: TASK-1 (KCNK3), TASK-2 (KCNK5), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), TRAAK (KCNK4), and TWIK-1 (KCNK1)—alternative nomenclature in parenthesis.
The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat- and cold-sensitive excitatory transient receptor potential (TRP) receptors, modulated by a thermal or chemical signal mostly via calcium ion channels. In an analogous manner, the mechano-gated and highly temperature-sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated in the role of sensory receptors. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. TRAAK and TREK-1 channels are expressed with thermo-TRP channels in sensory neurons, and control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK-1 controls heat responses of both capsaicin-sensitive and capsaicin-insensitive sensory neurons. Together TREK-1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol. The TREK-1 channel has been linked to the TRPV1 pain response and has been reported as co-expressed for this type of pain signal.
In U.S. Pat. No. 6,242,217, Glaxo disclosed the gene sequence for the human TREK-1 polypeptide.
In EP 1187627B1, agonists and antagonists to the TREK-1 channel were applied to the treatment of epilepsy, sleep-related disorders, the induction of sleep, cognitive dysfunction/enhancement, attention deficit disorder, addiction, anxiety/phobia, dyskinesias including Parkinson's, Huntington's chorea, Cerebral palsy, incontinence, erectile dysfunction, or alopecia.
In U.S. Pat. No. 7,625,562B2, the University of Keele disclosed an in vitro method for the generation of cartilage tissue from mammalian chondrocyte progenitor cells expressing mechanosensitive TWIK-related potassium (TREK) ion channels.
In WO 2006/066334A1, Adelaide Research & Innovation disclosed a method of modulating cardiac rhythm in a human subject, the method including the step of modulating the activity of TREK-1 and/or TREK-2 in the heart of the subject.
Although the TREK-1 potassium channel has been reported to be highly expressed in the brain, ovary and small intestine (WO 2006/066334A1), it has not been reported to be active in driving comfort response to a stimulus. None of the afore mentioned art disclosed the application of the TREK-1 potassium channel, its agonists or antagonists, for consumer product application. What is needed are TREK-1 agonists that can be used in products to positively influence consumer perception of the products and methods of determining TREK-1 agonist effectiveness.